Improving olaparib exposure to optimize adverse effects management.

Background: Olaparib is an inhibitor of the human poly-(ADP-ribose)-polymerase enzymes (PARP1/2) needed to repair single-strand DNA breaks. It is used in breast, ovarian, prostate and pancreatic cancer. Objectives: This work aimed to describe the pharmacokinetics/pharmacodynamics (PK/PD) relationship between olaparib plasma concentrations and common adverse effects (i.e. anaemia and hypercreatininaemia), in a real-life setting, to propose a target concentration for therapeutic drug monitoring. Methods: Two PK/PD models describing the evolution of haemoglobinaemia and creatininaemia as a function of time were developed, based on data from, respectively, 38 and 37 patients receiving olaparib. The final model estimates were used to calculate the incidence of anaemia and creatinine increase according to plasma trough concentrations for 1000 virtual subjects to define target exposure. Results: The final models correctly described the temporal evolution of haemoglobinaemia and creatininaemia for all patients. The haemoglobinaemia PK/PD model is inspired by Friberg's model, and the creatininaemia PK/PD model is an indirect response model. Model parameters were in agreement with physiological values and close to literature values for similar models. The mean (population) plasma haemoglobin concentration at treatment initiation, as estimated by the model, was 11.62 g/dL, while creatinine concentration was 71.91 µmol/L. Using simulations, we have identified a target trough concentration of 3500-4000 ng/mL, above which more than 20% of patients would report grade ≥3 anaemia. Conclusion: Based on real-world data, we were able to properly describe the time course of haemoglobinaemia and plasma creatininaemia during olaparib treatment.

Advanced prescription of injectable anticancer drugs: Safety assessment in a European Comprehensive Cancer Centre using the risk matrix approach.

AIMS: The purpose of this work was to assess failures in the advanced prescription of parenteral anticancer agents in an adult day oncology care unit with more than 100 patients per day. METHODS: An a priori descriptive analysis was carried out by using the risk matrix approach. After defining the scope in a multidisciplinary meeting, we determined at each step the failure modes (FMs), their effects (E) and their associated causes (C). A severity score (S) was assigned to all effects and a probability of occurrence (O) to all causes. These S and O indicators, were used to obtain a criticality index (CI) matrix. We assessed the risk control (RC) of each failure in order to define a residual criticality index (rCI) matrix. RESULTS: During risk analysis, 14 FMs were detected, and 61 scenarios were identified considering all possible effects and causes. Nine situations (15%) were highlighted with the maximum CI, 18 (30%) with a medium CI, and 34 (55%) with a negligible CI. Nevertheless, among all these critical situations, only three (5%) had an rCI to process (i.e., missed dose adjustment, multiple prescriptions and abnormal biology data); the others required monitoring only. Clinicians' and pharmacists' knowledge of these critical situations enables them to manage the associated risks. CONCLUSIONS: Advanced prescription of injectable anticancer drugs appears to be a safe practice for patients when combined with risk management. The major risks identified concerned missed dose adjustment, prescription duplication and lack of consideration for abnormal biology data.

Exploring the added value of pretherapeutic MR descriptors in predicting breast cancer pathologic complete response to neoadjuvant chemotherapy.

OBJECTIVES: To evaluate the association between pretreatment MRI descriptors and breast cancer (BC) pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Patients with BC treated by NAC with a breast MRI between 2016 and 2020 were included in this retrospective observational single-center study. MR studies were described using the standardized BI-RADS and breast edema score on T2-weighted MRI. Univariable and multivariable logistic regression analyses were performed to assess variables association with pCR according to residual cancer burden. Random forest classifiers were trained to predict pCR on a random split including 70% of the database and were validated on the remaining cases. RESULTS: Among 129 BC, 59 (46%) achieved pCR after NAC (luminal (n = 7/37, 19%), triple negative (n = 30/55, 55%), HER2 + (n = 22/37, 59%)). Clinical and biological items associated with pCR were BC subtype (p < 0.001), T stage 0/I/II (p = 0.008), higher Ki67 (p = 0.005), and higher tumor-infiltrating lymphocytes levels (p = 0.016). Univariate analysis showed that the following MRI features, oval or round shape (p = 0.047), unifocality (p = 0.026), non-spiculated margins (p = 0.018), no associated non-mass enhancement (p = 0.024), and a lower MRI size (p = 0.031), were significantly associated with pCR. Unifocality and non-spiculated margins remained independently associated with pCR at multivariable analysis. Adding significant MRI features to clinicobiological variables in random forest classifiers significantly increased sensitivity (0.67 versus 0.62), specificity (0.69 versus 0.67), and precision (0.71 versus 0.67) for pCR prediction. CONCLUSION: Non-spiculated margins and unifocality are independently associated with pCR and can increase models performance to predict BC response to NAC. CLINICAL RELEVANCE STATEMENT: A multimodal approach integrating pretreatment MRI features with clinicobiological predictors, including tumor-infiltrating lymphocytes, could be employed to develop machine learning models for identifying patients at risk of non-response. This may enable consideration of alternative therapeutic strategies to optimize treatment outcomes. KEY POINTS: • Unifocality and non-spiculated margins are independently associated with pCR at multivariable logistic regression analysis. • Breast edema score is associated with MR tumor size and TIL expression, not only in TN BC as previously reported, but also in luminal BC. • Adding significant MRI features to clinicobiological variables in machine learning classifiers significantly increased sensitivity, specificity, and precision for pCR prediction.

Oral Etoposide and Trastuzumab Use for HER2-Positive Metastatic Breast Cancer: A Retrospective Study from the Institut Curie Hospitals.

BACKGROUND: The TOP2A and ERBB2 genes are co-amplified in about 40% of HER2 positive (HER2+) breast cancers. Oral etoposide (VP16), an inhibitor of topoisomerase-II (encoded by TOP2A), has demonstrated clinical activity in metastatic breast cancer (MBC). The benefit of oral VP16 combined with trastuzumab (VP16-T) in HER2+ MBC has not yet been evaluated. METHODS: Patients treated at the Institut Curie Hospitals with VP16-T for HER2+ MBC were retrieved by an in silico search. Progression-free survival (PFS), overall survival (OS), response rate, prolonged PFS (defined as at least 6 months), clinical benefit, and toxicity were assessed. The co-amplification of ERBB2 and TOP2A was assessed by shallow whole genome sequencing on tumor tissue whenever available. RESULTS: Forty-three patients received VP16-T after a median number of six prior treatment lines for HER2+ MBC. Median PFS and OS were 2.9 months (95% CI [2.4-4.7]) and 11.3 months (95% CI [8.3-25.0]), respectively. Three patients had a complete response, while 12/40 (30%) experienced clinical benefit. Only three patients stopped treatment for toxicity. Seven (35%) patients displayed a TOP2A/ERBB2 co-amplification. No statistically significant correlation was found between outcome and TOP2A/ERBB2 co-amplification. CONCLUSION: Our analysis suggests a favorable efficacy and toxicity profile for VP16-T in patients with heavily pretreated HER2+ MBC.

[Homologous recombination deficiency and PARP inhibitors in therapeutics]. / Défauts de la recombinaison homologue et inhibiteurs de PARP en thérapeutique.

PARP inhibitors are effective in different types of tumors such as ovarian, breast, prostate and pancreatic cancer. Many studies are in progress and may lead to prescription evolution. PARP inhibitors prescription is almost reserved to patients with a constitutional BRCA mutation or a somatic BRCA alteration or a tumor with a deficiency in homologous recombination. Nowadays, the diagnosis of homologous recombination deficit, HRD, is possible with the prescription of a myChoice CDx (Myriad) test. PARP inhibitors are studied in association with chemotherapy and targeted therapies but also with radiotherapy and with immune checkpoint inhibitors. Access to PARP inhibitors is challenged with the emergence of resistance mechanism. Various trials are now studying the possibility of reversing these resistance mechanisms.

Prevalence of drug-drug interactions in sarcoma patients: key role of the pharmacist integration for toxicity risk management.

BACKGROUND: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment. PATIENTS AND METHODS: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software. RESULTS: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI.

Characteristics and Outcome of SARS-CoV-2 Infection in Cancer Patients.

BACKGROUND: Concerns have emerged about the higher risk of fatal coronavirus disease 2019 (COVID-19) in cancer patients. In this article, we review the experience of a comprehensive cancer center. METHODS: A prospective registry was set up at Institut Curie at the beginning of the COVID-19 pandemic. All cancer patients with suspected or proven COVID-19 were entered and actively followed for 28 days. RESULTS: Among 9842 patients treated at Institut Curie between March 13 and May 1, 2020, 141 (1.4%) were diagnosed with COVID-19, based on reverse transcription polymerase chain reaction testing and/or computerized tomography scan. In line with our case mix, breast cancer (40.4%) was the most common tumor type, followed by hematological and lung malignancies. Patients with active cancer therapy or/and advanced cancer accounted for 87.9% and 68.9% of patients, respectively. At diagnosis, 78.7% of patients had COVID-19-related symptoms, with an extent of lung parenchyma involvement inferior to 50% in 95.8% of patients. Blood count variations and C-reactive protein elevation were the most common laboratory abnormalities. Antibiotics and antiviral agents were administered in 48.2% and 6.4% of patients, respectively. At the time of analysis, 26 patients (18.4%) have died from COVID-19, and 100 (70.9%) were cured. Independent prognostic factors at the time of COVID-19 diagnosis associated with death or intensive care unit admission were extent of COVID-19 pneumonia and decreased O2 saturation. CONCLUSIONS: COVID-19 incidence and presentation in cancer patients appear to be very similar to those in the general population. The outcome of COVID-19 is primarily driven by the initial severity of infection rather than patient or cancer characteristics.

Adverse events of targeted therapies approved for women's cancers.

Breast cancer and gynecologic cancers affect >3 million women worldwide each year. With advances in precision medicine, a growing number of targeted therapies have been approved recently, and new therapeutic classes have emerged, including cell cycle inhibitors for hormone receptor positive breast cancer, antibody drug conjugate for human epidermal growth factor receptor 2 positive and triple negative breast cancer, and poly-ADP-ribose polymerase inhibitors for ovarian cancer. This article focuses first on the challenges for health care systems to address the specificities of each emerging targeted therapy and new issues raised by oral antitumor treatments, including individualization of prescriptions, drug-drug interaction assessment, pharmaceutical counseling, patient education, and outpatient management. Then, we provide an overview of the main adverse effects of targeted therapies approved for breast and gynecologic cancers, such as hematologic toxicity of cyclin-dependent kinase 4/6 inhibitors and poly-ADP-ribose polymerase inhibitors, metabolic disorders of phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin inhibitors, and cardiovascular toxicity of agents targeting human epidermal growth factor receptor 2.

COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.

BACKGROUND: Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France). METHODS: An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities. RESULTS: Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death. CONCLUSIONS: This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients.

Advances in theranostic biomarkers for tumor immunotherapy.

Cancer treatment has known a revolution with the emergence of immune checkpoint inhibitors. However, accurate theranostic biomarkers are lacking. In this review, we discuss different types of biomarkers currently under investigation. First, we focus on tissue biomarkers including PD-L1 expression by immunohistochemistry-the first Food and Drug Administration-approved biomarker-despite conflicting results. In addition, we report on novel biomarkers, including protein-based, molecular (tumor mutational load, immune signature…), circulating (neutrophil-to-lymphocyte ratio, serum cytokines…), and imaging-based biomarkers (radiomic signatures and positron-emission tomography using radiolabeled antibodies). We highlight the limitations of each candidate biomarker and finally discuss combinatorial approaches for their use and the opportunity to switch from a predictive strategy of biomarker research to an adaptive one in the field of cancer immunotherapy.

The impact of body composition parameters on severe toxicity of nivolumab.

BACKGROUND: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. METHODS: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). RESULTS: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 µg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. CONCLUSIONS: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort.

BACKGROUND: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. METHODS: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. RESULTS: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2). CONCLUSIONS: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.

Is there an Exposure-Response Relationship for Nivolumab in Real-World NSCLC Patients?

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small-cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman's rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02-3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78-36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46-27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

In the era of precision medicine, research of biomarkers for identification of responders to nivolumab therapy is a major challenge. Peripheral blood mononuclear cells (PBMC) could be an interesting surrogate tissue for identifying pharmacodynamic biomarkers. The aim of this exploratory study was to investigate the global serine/threonine kinase (STK) activity in PBMC from non-small-cell lung cancer (NSCLC) patients using a high throughput kinomic profiling method. PamChip® microarrays were used to explore the STK kinomic profile in PBMC from 28 NSCLC patients before nivolumab initiation (D0) and on day 14 (D14) of the first administration. Two clusters of patients (A and B) were identified at D0, median overall survival (OS) tended to be longer in cluster A than in B (402 vs. 112.5 days, respectively; p = 0.15). Interestingly, the PD-L1 tumor cell score (p = 0.045), the count of CD8+ cells (p = 0.023) and the total body weight (p = 0.038) were statistically different between the clusters. On D14, clusters C and D were identified. Greater activity of most STK, especially those of the PI3K/Akt signaling pathway, was noticed among cluster C. No significant difference between C and D was observed regarding OS. Considering the small number of patients, results from this preliminary study are not conclusive. However, the 4-fold longer median OS in cluster A paves the way to further investigate, in a larger cohort of NSCLC patients, the benefit of basal STK kinomic profile in PBMC to identify responders to nivolumab therapy.

Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib.

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75-300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug-drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.

[Issues of oral targeted therapies in daily clinical practice: 5th edition of the congress of pharmacology of anticancer drugs]. / Enjeux et écueils des thérapies ciblées orales en pratique clinique quotidienne : 5e journée de pharmacologie des anti-tumoraux.

Oral targeted therapies are a growing class of medication. After clinical trials conducted on a selected population, these molecules are usually approved at a fixed dose. However, oral tyrosine kinase inhibitors are characterized by a large intra and inter-individual pharmacokinetic variability, and a narrow therapeutic index. Hence, their prescription is hazardous and unsafe in non-selected people from daily clinical practice. The increasing number of available targeted therapies point out new challenges. These challenges should especially concern prescription for out of the ordinary patients, rules for dose adjustment according to factors of frailty. The ultimate goal is to ensure a safe and individualized prescription. Moreover, many of these molecules are metabolized by the CYP3A4, leading to a serious risk of drug interaction. These interactions might involve not only conventional medicine but also alternative and complementary medicines. These latter are more and more common but oncologists often lack experience about them. Finally, the oral route raises the issues of adherence, and the question of its assessment should now become a permanent part of patients care.